1. Field of the Invention
This invention relates generally to the fields of gene regulation and molecular medicine and more specifically to the regulation of cholesterol metabolism.
2. Background Information
Heart disease is the number one killer of people in developed countries and, along with stroke, accounts for more than half of the deaths due to pathological causes. Heart attacks usually occur when coronary arteries become narrowed due to atherosclerosis, which is initiated by the accumulation of cholesterol deposits on or within the cells of the blood vessel wall to form atherosclerotic plaques. As a result of the cholesterol accumulation and smooth muscle cell proliferation, a narrowing of the internal diameter of the blood vessel occurs and can reach a stage where blood can no longer circulate past the narrowed vessel. The incidence of stroke increases with the formation of atherosclerotic plaques. The result of blood vessel blockage is that cells that form the tissues downstream of the blockage die due to lack of oxygen or nutrition or to build-up of toxic metabolic waste products. As a result, cardiac function or brain function can be impaired.
One of the most important risk factors associated with atherosclerotic heart disease is the concentration in the blood of low density lipoprotein (LDL), which, in humans, is the major carrier of cholesterol in the form of cholesterol esters. Normally, LDL is cleared from the blood by the liver. However, in a subject having impaired expression of the LDL receptor (LDL-R), LDL clearance may be inadequate and the LDL concentration in the blood can increase. In addition, some people are genetically predisposed to having high LDL levels due, for example, to alterations in one of the many genes involved in the metabolic pathway for cholesterol and lipoprotein metabolism. As a result of each of these conditions, blood LDL levels are elevated or high density lipoprotein (HDL) levels are decreased, atherosclerosis develops and, in severe cases, a heart attack or stroke occurs.
In a person having a moderately high level of cholesterol in the blood, termed hypercholesterolemia, intervention therapy often can reduce cholesterol to a near normal level. For example, simple changes in the diet and initiation of a program of exercise can sometimes control blood levels of LDL and HDL. As the level of hypercholesterolemia increases, medical intervention becomes necessary. Various drugs that block cholesterol synthesis or increase the expression of hepatic LDL-R may decrease the blood cholesterol level. However, the available drugs suffer various shortcomings including lack of specificity, a lack of potency and adverse side effects.
Drug treatment cannot adequately reduce cholesterol blood levels in cases of extreme hypercholesterolemia or in cases where a genetic defect results in the inability to express hepatic LDL-R. In these cases, a liver transplant may offer the only reasonable hope of effectively treating a patient. For example, transplantation of a normal liver into a prematurely atherosclerotic female decreased plasma LDL levels to normal and resulted in a regression of atherosclerotic lesions (Bilheimer et al, New Engl. J. Med. 311: 1658-1664 (1984). Of course, the risks associated with transplantation are well documented. Recently, gene therapy has been reported to reduce the levels of cholesterol in a person having a genetic defect that resulted in severe hypercholesterolemia. However, methods for performing gene therapy remain experimental and have not been proven to be effective over a prolonged period of time.
Thus, a need exists for potent, specific agents that can effectively reduce blood cholesterol levels and, thereby, reduce or prevent the occurrence of heart attacks and strokes. The present invention satisfies this need and provides additional advantages as well.